Collaborative transplantation laboratory, Sydney Medical School and Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.
Nephrol Dial Transplant. 2013 Feb;28(2):327-36. doi: 10.1093/ndt/gfs453. Epub 2012 Dec 9.
Use of the mTOR inhibitor (mTORi) sirolimus to replace calcineurin inhibitors in kidney transplantation has been associated with improved renal function but, in a proportion of cases, also with de novo or exacerbated proteinuria. Experimental deficiency of vascular endothelial growth factor (VEGF) induces proteinuria and mTOR is required for VEGF production and signalling. We therefore explored the impact of sirolimus on the development of chronic allograft dysfunction (CAD) in the rat, with a focus on VEGF biology.
Lewis rats received F344 kidney allografts and were treated with 24 weeks of cyclosporine or sirolimus. Controls included allografts treated with cyclosporine for 10 days only and isografts treated with cyclosporine or sirolimus for 24 weeks. Kidney injury (proteinuria and histology) and expression of VEGF and VEGF-receptor (VEGFR; immunohistochemistry, laser capture micro-dissection and quantitative RT-PCR) were assessed.
Allograft controls developed proteinuria, tubulointerstitial fibrosis and atrophy, glomerulosclerosis, vasculopathy and leucocyte accumulation. Proteinuria was significantly reduced in both treatment groups but significantly more in cyclosporine treated animals. Tubulointerstitial damage, glomerulosclerosis and leucocyte accumulation were significantly attenuated in both treatment groups; however, vasculopathy was reduced only by sirolimus. Significantly diminished expression of VEGF and VEGFR mRNA and protein was evident in the sirolimus group. In vitro, sirolimus reduced VEGF production by podocytes (P < 0.05) and inhibited VEGF-induced proliferation of podocytes, endothelial and mesangial cells.
Cyclosporine and sirolimus retard development of CAD in this rat model. Sirolimus exhibits greater protection against vasculopathy but induces proteinuria; effects are likely to be related to inhibition of VEGF signalling.
在肾移植中，使用 mTOR 抑制剂（mTORi）西罗莫司替代钙调神经磷酸酶抑制剂与肾功能改善相关，但在一部分病例中，也会导致新出现或加重的蛋白尿。血管内皮生长因子（VEGF）的实验性缺乏会导致蛋白尿，而 mTOR 是 VEGF 产生和信号传导所必需的。因此，我们研究了西罗莫司对大鼠慢性移植物功能障碍（CAD）发展的影响，重点关注 VEGF 生物学。
Lewis 大鼠接受 F344 肾同种异体移植，并接受 24 周的环孢素或西罗莫司治疗。对照组包括仅接受环孢素治疗 10 天的同种异体移植物和接受环孢素或西罗莫司治疗 24 周的同基因移植物。通过蛋白尿和组织学评估肾脏损伤，以及 VEGF 和 VEGF 受体（VEGFR；免疫组织化学、激光捕获微切割和定量 RT-PCR）的表达。
同种异体移植物对照组出现蛋白尿、肾小管间质纤维化和萎缩、肾小球硬化、血管病变和白细胞积聚。两种治疗组的蛋白尿均显著减少，但环孢素治疗组减少更为显著。两种治疗组的肾小管间质损伤、肾小球硬化和白细胞积聚均显著减轻；然而，只有西罗莫司可减轻血管病变。西罗莫司组 VEGF 和 VEGFR mRNA 和蛋白的表达明显减少。在体外，西罗莫司可减少足细胞的 VEGF 产生（P<0.05），并抑制 VEGF 诱导的足细胞、内皮细胞和系膜细胞增殖。
环孢素和西罗莫司可延缓该大鼠模型中 CAD 的发展。西罗莫司对血管病变表现出更大的保护作用，但会导致蛋白尿；这些作用可能与抑制 VEGF 信号有关。
